Impaired healing, occurring in approximately 630,000 fractures annually in the U.S., is physically disabling, costly, and poorly understood. Bone heals through formation of new bone rather than scar tissue; thus, similarities between fetal skeletal development and adult repair can be used to understand fracture healing. In both development and healing, bone forms through two mechanisms, the direct formation of bone (intramembranous ossification) and the formation of bone through a cartilage intermediate (endochondral ossification). The primary mode of healing is determined during the earliest stages of repair (inflammatory stage), as mesenchymal cells at the site of injury differentiate into osteoblasts or chondrocytes based on conditions present at the fracture site. One major determinant of progenitor cell differentiation is mechanical stability. Stabilized fractures heal predominantly by recapitulating embryonic intramembranous ossification while non-stabilized fractures heal by reinitiating endochondral ossification. Preliminary work suggests that the early events that stimulate repair, such as inflammation and angiogenesis, differ significantly in the stabilized and non-stabilized fracture environments. We hypothesize that these differences produce distinct conditions that govern mesenchymal cell differentiation into osteoblasts or chondrocytes. The aims of this proposal are: i) to determine the post-injury inflammatory and angiogenic responses between stabilized and non-stabilized fracture healing; 2) to identify the extent to which inflammation and angiogenesis regulate skeletal repair; and 3) to establish the relation between inflammation and angiogenesis to the differentiation of progenitor cells during fracture repair. We will use cellular, molecular, and genetic approaches to achieve these aims. This proposal will examine the role of the inflammatory response and vascular repair during bone healing. Bydefining these processes, we will better understand the way fractures heal and the mechanism by which cells decide to become bone or cartilage. Our goal is to use the findings from these studies to develop new treatments to stimulate fracture healing.